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Studies and Synthesis of Syringolin A, Functionalized Thiadiazines, and Thiol Additions to Enones

Rosenker, Christopher J (2013) Studies and Synthesis of Syringolin A, Functionalized Thiadiazines, and Thiol Additions to Enones. Doctoral Dissertation, University of Pittsburgh. (Unpublished)

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Part one of this dissertation describes the formal synthesis of syringolin A. Syringolin A contains a unique 12-membered dipeptide core and has been shown to be a potent irreversible proteasome inhibitor. Completion of the formal synthesis of syringolin A was facilitated by the rapid access to non-proteinogenic α,β-unsaturated-γ-amino acid and α-amino acid fragments with complete stereochemical control utilizing the stereoselective addition of alkenylorganometallic reagents to chiral N-tert-butanesulfinylimines.
Part two discusses the development of a robust strategy for the preparation and selective functionalization of heterocyclic thiadiazines with four points of diversity. Hydrolysis of the pendant C-4 ester and functionalization of the resulting acid provided access to a small library of highly substituted thiadiazine analogues that exhibit favorable physicochemical properties for drug-like compounds.
Part three describes the investigation of the equilibria of thiophenol conjugate additions to enone-containing indole scaffolds. Our studies indicate that mono-β-substituted enones form thermodynamically favorable adducts with thiophenol. We also found that thiol eliminations to form enones are favorable in the presence of DBU but not Et3N. These experiments suggest that mono-β-substituted enones could be used as irreversible covalent protein modifiers.


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Item Type: University of Pittsburgh ETD
Status: Unpublished
CreatorsEmailPitt UsernameORCID
Rosenker, Christopher
ETD Committee:
TitleMemberEmail AddressPitt UsernameORCID
Committee ChairWipf, Peterpwipf@pitt.eduPWIPF
Committee MemberDay, Billy Wbday@pitt.eduBDAY
Committee MemberNelson, Scott Gsgnelson@pitt.eduSGNELSON
Committee MemberGold, Barrygoldbi@pitt.eduGOLDBI
Date: 2 July 2013
Date Type: Publication
Defense Date: 10 December 2012
Approval Date: 2 July 2013
Submission Date: 13 December 2012
Access Restriction: No restriction; Release the ETD for access worldwide immediately.
Number of Pages: 196
Institution: University of Pittsburgh
Schools and Programs: Dietrich School of Arts and Sciences > Chemistry
Degree: PhD - Doctor of Philosophy
Thesis Type: Doctoral Dissertation
Refereed: Yes
Uncontrolled Keywords: Syringolin Total Synthesis Heterocycles Thiadiazine Thiol conjugate addition Enone addition equilibrium
Date Deposited: 02 Jul 2013 14:39
Last Modified: 15 Nov 2016 14:08


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